The present invention relates generally to medical devices and methods, chemical and biological sample manipulation, spectrometry, drug discovery, and related research. More specifically, the invention relates to an interface between microfluidic devices and a mass spectrometer.
The use of microfluidic devices such as microfluidic chips is becoming increasingly common for such applications as analytical chemistry research, medical diagnostics and the like. Microfluidic devices are generally quite promising for applications such as proteomics and genomics, where sample sizes may be very small and analyzed substances very expensive. One way to analyze substances using microfluidic devices is to pass the substances from the devices to a mass spectrometer (MS). Such a technique benefits from an interface between the microfluidic device and the MS, particularly MS systems that employ electrospray ionization (ESI).
Electrospray ionization generates ions for mass spectrometric analysis. Some of the advantages of ESI include its ability to produce ions from a wide variety of samples such as proteins, peptides, small molecules, drugs and the like, and its ability to transfer a sample from the liquid phase to the gas phase, which may be used for coupling other chemical separation methods, such as capillary electrophoresis (CE), liquid chromatography (LC), or capillary electrochromatography (CEC) with mass spectrometry. Devices for interfacing microfluidic structures with ESI MS sources currently exist, but these existing interface devices have several disadvantages.
One drawback of currently available microfluidic MS interface structures is that they typically make use of an ESI tip attached to the microfluidic substrate. These ESI tips are often sharp, protrude from an edge of the substrate used to make the microfluidic device, or both. Such ESI tips are both difficult to manufacture and easy to break or damage. Creating a sharp ESI tip often requires sawing each microfluidic device individually or alternative, equally labor intensive manufacturing processes. Another manufacturing technique, for example, involves inserting a fused-silica capillary tube into a microfluidic device to form a nozzle. This process can be labor intensive, with precise drilling of a hole in a microfluidic device and insertion of the capillary tube into the hole. The complexity of this process can make such microfluidic chips expensive, particularly when the microfluidic device is disposable which leads to concern over cross-contamination of substances analyzed on the same chip.
Other currently available microfluidic devices are manufactured from elastomers such as polydimethylsiloxane (PDMS) and other materials that provide less fragile tips than those just described. These types of materials, however, are generally not chemically resistant to the organic solvents typically used for electrospray ionization.
Another drawback of current microfluidic devices involve dead volume at the junction of the capillary tube with the rest of the device. Many microfluidic devices intended for coupling to a mass spectrometer using an ESI tip have been fabricated from fused silica, quartz, or a type of glass such as soda-lime glass or borosilicate glass. The most practical and cost-effective method currently used to make channels in substrates is isotropic wet chemical etching, which is very limited in the range of shapes it can produce. Plasma etching of glass or quartz is possible, but is still too slow and expensive to be practical. Sharp shapes such as a tip cannot readily be produced with isotropic etching, and thus researchers have resorted to inserting fused-silica capillary tubes into glass or quartz chips, as mentioned above. In addition to being labor-intensive, this configuration can also introduce a certain dead volume at the junction, which will have a negative effect on separations carried out on the chip.
Some techniques for manufacturing microfluidic devices have attempted to use the flat edge of a chip as an ESI emitter. Unfortunately, substances would spread from the opening of the emitter to cover much or all of the edge of the chip, rather than spraying in a desired direction and manner toward an MS device. This spread along the edge causes problems such as difficulty initiating a spray, high dead volume, and a high flow rate required to sustain a spray.
Another problem sometimes encountered in currently available microfluidic ESI devices is how to apply a potential to substances in a device with a stable ionization current while minimizing dead volume and minimizing or preventing the production of bubbles in the channels or in the droplet at the channel outlet. A potential may be applied to substances, for example, to move them through the microchannel in a microfluidic device, to separate substances, to provide electrospray ionization, or typically a combination of all three of these functions. Some microfluidic devices use a conductive coating on the outer surface of the chip or capillary to achieve this purpose. The conductive coating, however, often erodes or is otherwise not reproducible. Furthermore, bubbles are often generated in currently available devices during water electrolysis and/or redox reactions of analytes. Such bubbles adversely affect the ability of an ESI device to provide substances to a mass spectrometer in the form of a spray having a desired shape.
Therefore, it would be desirable to have microfluidic devices which provide electrospray ionization of substances to mass spectrometers and which are easily manufactured. Ideally, such microfluidic devices would include means for electrospray ionization that provide desired spray patterns to an MS device and that could be produced by simple techniques such as dicing multiple microfluidic devices from a common substrate. In addition to being easily manufactured, such microfluidic devices would also ideally include means for emitting substances that do not include protruding tips that are easily susceptible to breakage. Also ideally, microfluidic devices would include means for providing a charge to substances without generating bubbles and while minimizing dead volume. At least some of these objectives will be met by the present invention.